1. Field of the Invention
This invention is in the field of medicinal chemistry. In particular, the invention relates to 1-(arylmethyl)-5,6,7,8-tetrahydroquinazoline-2,4-diones and analogs, and the use of these compounds as poly (ADP-ribose) polymerase (PARP) inhibitors and anti-cancer drugs.
2. Related Art
Poly (ADP-ribose) polymerase (PARP) catalyzes the addition of poly (ADP-ribose) to the target protein using NAD+ that is an important process in DNA repair. This is an essential process for maintaining DNA and chromosome integrity and stability, and for ensuring the survival of mammalian cells. PARP-1 catalyzes the majority of the intracellular ADP-ribose polymerization reactions, although PARP-2 and other subtypes also have this function. The PARP-1 knockout mice do not have the repair function for single-stranded DNA damages (Krishnakumar and Kraus. 2010, Molecular Cell 39:8). Cancer cells with DNA repair defects, such as BRCA1 (breast cancer 1) or BRCA2 (breast cancer 2) deficiency, are particularly sensitive to DNA damaging anticancer agents, including platinum chemotherapy drugs, DNA methylation anticancer drugs and DNA topoisomerase inhibitors, or radiation therapy. Phase II clinical trial data have shown that PARP-1 inhibitor olaparib (AZD2281) was effective for the treatment of advanced breast cancer (Andrew Tutt et al., 2009, J. Clin. Oncol 27:18 s; Andrew Tutt et al., 2010 Lancet 376:235; RA Dent et al., 2010 J. Clin. Oncol. 28:15 s). These scientific and clinical results demonstrated that PARP-1 inhibitors may be used as effective anti-cancer drugs to treat a variety of cancers. The applications of PARP-1 inhibitors for the treatment of cancer are mainly based on two mechanisms. First, because of the rapid growth, DNA replication is much higher in cancer cells than in normal cells. Drugs that cause DNA damage will induce cancer cell death selectively. However, due to the presence of DNA repair enzymes, the therapeutic effects of these drugs cannot be fully materialized. By inhibiting the DNA repair mechanism, PARP-1 inhibitors in combination with commonly used DNA damaging anti-cancer drugs, such as temozolomide, can achieve synergy effects and greatly enhance the anticancer effects of currently used anticancer drugs. Second, for cancer cells with DNA repair deficiency, such as BRCA1 or BRCA2 deficient triple-negative breast cancer, PARP-1 inhibitors can directly kill the cancer cells and function as anticancer drugs independently. According to statistics, about 10-15% of breast cancer patients have family history of genetic factors, in which the BRCA1 or BRCA2 gene mutations account for 15-20% of all hereditary breast cancers. Since PARP-1 is involved in DNA repair, utilization of PARP-1 inhibitors to inhibit DNA repair may he an effective and selective treatment for cancers with DNA repair genetic defect, including triple-negative breast cancers. Furthermore, PARP-1 inhibitors may also be used to treat diseases due to excessive cell death, including central nervous system diseases such as stroke and neurodegenerative diseases (Akinori Iwashita et al., 2004, J. Pharmacol. Exp. Thera. 310: 425).
The inhibitory activity of PARP-1 inhibitors can be measured by directly using PARP-1 enzymes. In addition, since PARP-1 inhibitors can increase the cytotoxicity of DNA damaging anti-cancer drugs such as methyl mathanesulfonate (MMS) on cancer cells, the activity of PARP-1 inhibitors can also be determined by measuring cell viability, such as using a MTT assay, in the presence of DNA damaging anti-cancer drugs.
It has been known that many cancer chemotherapeutic drugs trigger cancer cells to undergo apoptosis. The mechanism of apoptosis involves the activation of a series of proteolytic enzymes called caspases. Caspases are cysteine-aspartate proteases, a main group of enzymes playing key functions in apoptosis, which generally exist in the cell in the inactive zymogen state. They are specific for the hydrolysis of the peptide bond with aspartic acid residues at the P1 position of substrates. Among these caspases, caspase-3, 6, and 7 are key effector caspases that cleave multiple protein substrates in cells, leading to cell death. Cellular caspase activity can be determined using fluorescent caspase substrates. PARP-1 inhibitors can increase the apoptosis-inducing activity of many DNA damaging anticancer drugs such as MMS. Therefore, the activity of PARP-1 inhibitors can be determined via measuring the intracelluar caspase activity of cancer cells, in the presence DNA damaging anticancer drugs.                WO2003059892 disclosed tetrahydroquinazolinediones and analogs as poly(ADP-ribose) polymerase (PARP) inhibitors, wherein A=CH2, O, S; X=alkylene, which may be replaced by oxygroup; R1=H, alkoxycarbonyl; R2=(un)substituted aryl and heteroaryl, which may be substituted by NO2, halo, CN, etc.        
                WO2002040455 disclosed the preparation of amidoalkyl uracil derivatives as PARP inhibitors, wherein A=D, CH2D, DCH2, CH:CHCH2, CH2CH:CH, CH2CH2D, DCH2CH2, CH2DCH2; D=CH2, O, S; E, G=substituted alkenyl, cycloalkenyl; T=CH2; U, V=substituted aryl, heteroaryl; W═O, S, CO2, OCO, NR4; R4═H, alkyl; m, n, q, p=0, 1; X═O, S, NR5; R5═H, alkyl, PhCH2; Y1═H; Y2═OH; S; Y1Y2=O, S, NR6; R6=H, alkyl, PhCH2; R1═H, alkyl, halo-substituted cycloalkyl: R2═H, alkoxycarbonyl; R3=substituted aryl, heteroaryl.        
                WO2002006247 disclosed the preparation of fused amidoalkyl uracil derivatives as PARP inhibitors, wherein A=D, CH2D, DCH2, CH:CHCH2, CH2CH:CH, CH2CH2D, DCH2CH2, CH2DCH2; D=CH2, O, S; X=substituted alkenyl, cycloalkenyl; R1═H, haloalkyl, cycloalkyl; R2=SO2R4, SO2NR5R6, COR7, CONR8R9, CO2R10; substituted alkyl, cycloalkyl, GE; E=substituted aryl, heterocyclic group, G is (un)substituted aryl, heteroaryl; R5, R6=H, substituted cycloalkyl, alkyl, aryl, heteroaryl; or R5R6=substituted heterocyclic group; R7=substituted alkyl, cycloalkyl; GE (as above); R8, R9═H, substituted alkyl, cycloalkyl; or R8R9=substituted heteroaryl; R10=substituted alkyl, cycloalkyl, aryl; or R1R2=mono or disubstituted heterocylic group; R3═H, alkoxycarbonyl.        
